Amol Akhade: Key Insights from WCLC25

Amol Akhade, Senior Consultant at Fortis Hospitals Mumbai, highlighted emerging data and clinical insights from WCLC25 in lung cancer.

“Toripalimab consolidation after CCRT in LS-SCLC at WCLC25

Small, single-institution phase II (N=98) reports impressive outcomes:

• PFS HR 0.54 (NR vs 14m, p=0.03)
• OS HR 0.41 (NR vs 30m, p=0.01)
• ↓ brain progression (HR 0.47)
• 2y OS ~79% vs 59%.

At first glance, outcomes look stronger than ADRIATIC (durvalumab, phase III, N=749, global) where:

• PFS HR 0.76
• OS HR 0.70 (56 vs 33m)
• Brain relapse HR 0.64

But context matters

1. Design: Toripalimab = single center, phase II, only 98 patients, 6m of IO. ADRIATIC = global, phase III, 749 pts, 24m IO.
2. Population: 100% Asian vs 50% Asian, 50% rest of world in ADRIATIC.
3. Endpoints: Toripalimab = PFS primary; ADRIATIC = OS and PFS co-primary.
4. PCI effect: OS benefit stronger in those without PCI → raises question if CNS protection is the real driver.
5. Follow-up: OS NR, risk of attenuation with maturity.

Critical view:

Signal is promising, especially for CNS outcomes.

But small, immature trial → likely overestimation of effect sizes.

ADRIATIC remains definitive standard.

Key unresolved question: is 6 months of IO enough, or is 24 months needed for durable control?

For now → Toripalimab may be a potential LMIC option (shorter, cheaper), but only phase III validation will tell if ‘less is more.’”

“FLAURA2 Final OS at WCLC25

• 1L EGFRm NSCLC: Osi+Chemo vs Osi alone
• mOS 47.5 vs 37.6 mo
• HR 0.77 (95% CI 0.61–0.96; p=0.02)
• 3-yr OS: 63% vs 51%

Benefit consistent across subgroups

• AEs: manageable, Osi discontinuation 12% vs 7%
• Adds ~10 mo survival, but at cost of prolonged pemetrexed and real-world feasibility issues.

Takeaway: Osi+Chemo is new SOC, but Osi mono (mOS 37.6 mo) remains excellent for selected patients”

“Data that we all were waiting for (ivonescimab + chemo post-osimertinib):

HARMONi-A at WCLC25 – ivonescimab (PD-1/VEGF bispecific) + chemo vs chemo after 3rd-gen EGFR-TKI progression

• mPFS 6.8 vs 4.4 mo (HR 0.52, p<0.001)
• ORR 44.7% vs 34.2%
• Intracranial PFS benefit (HR 0.34 in BM patients)
• mOS 16.8 vs 14.0 mo (HR 0.79, p=0.057) → trend, not statistically sig.
  Grade ≥3 TRAEs: 50% vs 42% (mainly VEGF-related, manageable)

Takeaway: Strong PFS + intracranial signal, OS trending positive but missed significance. Clinically relevant in EGFRm NSCLC post-TKI, esp. for brain mets.

Regulatory and real-world adoption may hinge on further OS update?

Or is this the final full stop?”

“Excellent slide to show standard 1st line treatment for advanced NSCLC with mEGFR.”

“ACROSS-2 at WCLC25.

Phase III | 1L EGFRm NSCLC with concomitant tumor suppressor gene (TSG) alterations

Design: Aumolertinib 110 mg QD ± platinum/pemetrexed (induction → maintenance)

N=126 (62 combo / 64 mono)

Median FU: 25.3 mo

Efficacy

• mPFS 19.8 vs 16.5 mo
• HR 0.55 (95% CI 0.34–0.91; p=0.02)
• OS immature
• PFS gain notable in this poor-risk biology (TSG+) group

Safety

• Common AEs ≥20%: cytopenias, ↑AST/ALT, ↑CK, nausea, rash
• No new safety signals, manageable profile

Takeaway: First RCT dedicated to EGFRm + TSG patients Aumolertinib+chemo delivered a statistically significant PFS improvement vs TKI alone, with tolerable safety.

Adds weight to the growing TKI+chemo intensification paradigm (echoes FLAURA2).”

“ARROS-1 at WCLC25 – Zidesamtinib, next-gen ROS1 TKI (brain-penetrant, TRK-sparing)

TKI-pretreated (n=117)

• ORR 44%
• DOR ≥6 mo 84%, ≥12 mo 78%, ≥18 mo 62%

CNS disease: IC-ORR 48%, IC-DOR ≥12 mo 71%

G2032R mutation: ORR 54%, durable responses

• TKI-naïve (n=35, prelim)
• ORR 89% (31/35)
• 12-mo DOR 96%
• IC-ORR 83% (4 CRs), no CNS progression events

Safety (N=432): Mostly mild—edema, constipation, ↑CPK, fatigue. Gr≥3 events rare; 10% dose reduction, 2% discontinuation.

Takeaway: Durable systemic + CNS activity, including in heavily pretreated and G2032R+ patients Zidesamtinib emerging as a strong candidate in resistant ROS1+ NSCLC, with promise even in naïve disease.”

“Is this the end or beginning for ivonescimab?”

“E4512/ALCHEMIST at WCLC25

Adjuvant crizotinib vs observation in resected stage II–IIIB ALK+ NSCLC

• N=166 (2014–2024, accrual stopped after adjuvant alectinib approval)
• Median FU: 58 mo
• Median DFS: 72.8 mo (criz) vs 75.1 mo (obs)
• HR 1.06 (95% CI 0.63–1.77; p=0.86) → no benefit
• OS: Not reached, HR 0.49 (p=0.26)

Toxicity:

• 34% G3 AEs (diarrhea 6%, edema 4%);
• 1% G4 stroke
• 25% discontinued criz due to AEs;
• median exposure only 13.5 mo

Takeaway: Adjuvant crizotinib failed to improve DFS, with high discontinuation rates. Confirms why 1st-gen TKIs are obsolete in early-stage ALK NSCLC.

Adjuvant alectinib (ALINA) now the true standard.”

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